Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][CH2:18][CH3:19])[CH2:11][C:10]2[C:5](=[C:6]([Cl:15])[C:7]([Cl:14])=[C:8]([O:12]C)[CH:9]=2)[C:4]1=[O:16])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-]>CCCCCCC>[CH2:1]([C:3]1([CH2:17][CH2:18][CH3:19])[CH2:11][C:10]2[C:5](=[C:6]([Cl:15])[C:7]([Cl:14])=[C:8]([OH:12])[CH:9]=2)[C:4]1=[O:16])[CH3:2]
Reactant: CCCC1(CC)Cc2cc(OC)c(Cl)c(Cl)c2C1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Product: CCCC1(CC)Cc2cc(O)c(Cl)c(Cl)c2C1=O

Procedure:
2-Ethyl-2-n-propyl-5-hydroxy-6,7-dichloro-1-indanone is prepared following substantially the same procedure described in Example 5, Step F, using the following substances: 2-ethyl-2-n-propyl-5methoxy-6,7-dichloro-1-indanone (11 g., .037 mole), aluminum chloride (12.5 g., 0.094 mole) and heptane (400 ml.). The above procedure gives 9.0 g. of 2-ethyl-2-n-propyl-5-hydroxy-6,7-dichloro-1-indanone which after recrystallization from methylcyclohexane melts at 153° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[C:18]1([S:24]([O-:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:27](=[O:34])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH2:28].C(O)=O>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]([NH:28][C:27](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[S:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:26])=[O:25])[CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: O=CO
Product: CC(C)(C)OC(=O)NC(c1cccc(OCc2ccccc2)c1)S(=O)(=O)c1ccccc1
Reaction time: 96 h
Yield: 67.6 %

Procedure:
To 3-(benzyloxy)benzaldehyde (5 g, 23.6 mmol) and benzenesulfinic acid sodium salt (3.9 g, 23.6 mmol) in THF (23 mL) was added water (51.5 mL), tert-butyl carbamate (2.76 g, 23.6 mmol) and formic acid (2.66 mL, 70 mmol). The mixture was stirred for 4 day and filtrated. The precipitate was washed with water and triturated in hexane containing 9% dichloromethane. After filtration the solids were dried in vacuum to yield 7.24 g of tert-butyl {[3-(benzyloxy)phenyl](phenylsulfonyl)methyl}carbamate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=2)[N:19]=4)[C@H:10]([OH:36])[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.CO.O1CCOCC1>[CH:31]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[C:17]4[CH:34]=[CH:35][C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH:10]5[OH:36])=[CH:15][C:16]=4[O:25][CH2:24][CH2:23][N:22]3[CH:21]=2)=[N:30][CH:29]=[N:28]1)([CH3:33])[CH3:32]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc([C@@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3O)cc1OCC2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3O)cc1OCC2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of trans-racemic-3-hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (180 mg, 0.36 mmol) in DCM (1 mL) and methanol (0.6 mL) was added 4M HCl in dioxane (1.6 mL) slowly and the reaction mixture stirred at RT for 2.5 hr before being concentrated in vacuo. The resultant residue was triturated in diethyl ether to give 4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-3-ol which was resolved to give the (3R,4R) enantiomer 303 as a white solid (172 mg, quantitative). LCMS: RT=2.41 min, [M+H]+ 395. 1H NMR 400 MHz (DMSO-d6) δ: 9.30 (1H, br, s), 9.10 (1H, br, s), 8.36 (1H, d, J=8.28 Hz), 8.10 (1H, br, s), 8.06 (1H, s), 7.04 (1H, d, J=8.38 Hz), 6.91 (1H, s), 5.87 (1H, m), 4.53 (4H, d, J=8.12 Hz), 3.90 (1H, br, m), 3.25 (2H, m), 2.78 (1H, m), 2.52 (2H, m), 1.80 (2H, m), 1.50 (1H, d, J=6.58 Hz)
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=O.[C:12](Cl)(=O)C(Cl)=O.[CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[C:22]=1[OH:30])([CH3:20])[CH3:19].[Cl-].[Al+3].[Cl-].[Cl-]>O1CCCC1.ClCCCl>[CH2:11]([O:10][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:25]1[CH:26]=[C:21]([CH:18]([CH3:20])[CH3:19])[C:22]([OH:30])=[C:23]([CH:27]([CH3:29])[CH3:28])[CH:24]=1)=[O:8])[CH3:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)CCCCC(=O)[O-]
Reactant: CC(C)c1cccc(C(C)C)c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCOC(=O)CCCCC(=O)c1cc(C(C)C)c(O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Monomethyl adipate (61 g, 350 mmol) was treated with excess oxalyl chloride in tetrahydrofuran. The mixture was concentrated, and the resulting acid chloride was mixed with 2,6-Diisopropyl phenol (57 g, 350 mmol) at 0° C. Aluminum chloride (93 g, 700 mmol) and a catalytic amount of 1,2-dichloroethane were added in portions, and the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with 1 M HCl and extracted with ethyl acetate. Concentrated in vacuo and chromatographed the residue to give the expected product.
Reaction SMILES: O[CH:2]([CH:8]1[O:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[C:20]3[N:21]([CH:25]=[CH:26][N:27]=3)[CH:22]=[CH:23][CH:24]=2)[C:9]1=[O:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>N1C=CC=CC=1.C(OC(=O)C)(=O)C.ClCCl>[CH:2](=[C:8]1[O:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[C:20]3[N:21]([CH:25]=[CH:26][N:27]=3)[CH:22]=[CH:23][CH:24]=2)[C:9]1=[O:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(O)C1OC(=O)N(CCCCOc2cccn3ccnc23)C1=O
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCC=C1OC(=O)N(CCCCOc2cccn3ccnc23)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 386 mg (0.99 mmol) of 5-(1-hydroxyhexyl)-3-[4-(imidazo[1,2-a]pyridin-8-yloxy)butyl]oxazolidine-2,4-dione in 8 ml of pyridine, 4 ml of acetic anhydride was added, followed by stirring at room temperature for 2 hours and then at 90° C. for 21 hours. The mixture was dissolved in dichloromethane, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate/hexane=4/1→ethyl acetate) to yield 79.2 mg (22%, yellow oily substance) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=2)[CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][C:22]([F:21])([F:32])[F:33])=[CH:25][CH:26]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CCc1cnc(NCCc2ccc(OC)c(Br)c2)nc1
Product: CCc1cnc(N(CCc2ccc(O)c(Br)c2)Cc2ccc(OC(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from N-[2-(3-bromo-4-methoxyphenyl)ethyl]-5-ethylpyrimidin-2-amine and 4-trifluoromethoxy benzyl bromide.
Reaction SMILES: [C:1]1([C@H:7]([CH3:11])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:32])[C:18]=1[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)=[O:21]>>[Cl:32][C:17]1[CH:16]=[N:15][CH:14]=[C:13]([Cl:12])[C:18]=1/[CH:19]=[C:20](\[O:21][C:8](=[O:9])[C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11])/[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1
Reactant: C[C@H](C(=O)Cl)c1ccccc1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC
Product: COc1ccc(/C(=C/c2c(Cl)cncc2Cl)OC(=O)[C@@H](C)c2ccccc2)cc1OC

Procedure:
The compound was obtained starting from 2-(S)-phenyl-propionyl chloride and 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl) -ethanone, following the procedure of Example 7.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:19]=2[C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH2:10][CH2:9]1.[CH3:30][S:31]([Cl:34])(=[O:33])=[O:32]>N1C=CC=CC=1>[ClH:34].[CH3:30][S:31]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:19]=2[C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH2:10][CH2:9]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(NCCCN2CCN(c3ccccc3N)CC2)c(C(=O)N(C)C)c1
Solvent: c1ccncc1
Product: Cc1ccc(NCCCN2CCN(c3ccccc3NS(C)(=O)=O)CC2)c(C(=O)N(C)C)c1
Product: Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2-{3-[4-(2-aminophenyl)piperazin-1-yl]propylamino}-N,N,5-trimethylbenzamide (398 mg, 1.01 mmol), prepared as in Example 36, in 10 mL of pyridine was cooled to 0° C. and methanesulfonyl chloride (0.08 mL, 1.03 mmol) was added slowly. The mixture was stirred at 0° C. for 2 hours and then evaporated to dryness. The residue was partioned between saturated sodium bicarbonate and ethyl acetate. The organic layer was separated, dried (K2CO3) and evaporated to dryness. The residue was purified on silica gel by column chromatography eluting with 5% methanol/methylene chloride to give 2-{3-[4-(2-methylsulfonylaminophenyl)-piperazin-1-yl]propylamino}-N,N,5-trimethylbenzamide hydrochloride, m.p. 207°-209° C.; Anal.: Calcd. for C24H35N5O3S.(HCl)2.(H2 O)0.5 : C, 51.89; H, 6.90; N, 12.61%; Found: C, 51.9; H, 6.74.; N, 12.56%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>O>[C:11]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:10])[CH:7]([CH3:9])[CH3:8])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4.0 g. L-valine methyl ester hydrochloride dissolved in 25 ml water was added 3.35 g. benzoyl chloride while keeping the pH of the solution at approximately 8-9 with 1 N NaOH. The addition of the reactants took approximately 2 hours. Following addition of the reactants the reaction mixture was stirred at about 25° C. for 4 hours and then cooled to about 0° C. for 16 hours. The precipitated solid was collected and the filtrate was extracted twice with ether. The above collected solid was dissolved in this ether solution, which was then washed with a saturated sodium bicarbonate solution. The organic phase was dried and concentrated to give a white solid.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][N:11]=3)[N:6]([C@H:13]3[CH2:16][C@H:15]([NH:17][C:18]4[S:19][C:20]([C:23](O)=[O:24])=[CH:21][N:22]=4)[CH2:14]3)[C:5]2=[O:26])[CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.[N:34]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)[C:38]2C=C[CH:41]=[CH:42][C:37]=2[N:36]=N1.C(N(C(C)C)CC)(C)C.Cl.NC1(C#N)CC1>C(Cl)Cl>[C:38]([C:37]1([NH:36][C:23]([C:20]2[S:19][C:18]([NH:17][C@H:15]3[CH2:16][C@H:13]([N:6]4[C:7]5=[N:8][CH:9]=[CH:10][N:11]=[C:12]5[N:4]([CH:1]5[CH2:2][CH2:3]5)[C:5]4=[O:26])[CH2:14]3)=[N:22][CH:21]=2)=[O:24])[CH2:41][CH2:42]1)#[N:34]
Reactant: O=C(O)c1cnc(N[C@H]2C[C@H](n3c(=O)n(C4CC4)c4nccnc43)C2)s1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CC1(N)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(NC(=O)c2cnc(N[C@H]3C[C@H](n4c(=O)n(C5CC5)c5nccnc54)C3)s2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2-((trans-3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclobutyl)amino)thiazole-5-carboxylic acid, (EXAMPLE 149), (0.070 g, 0.188 mmol), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.147 g, 0.282 mmol), diisopropylethylamine (0.049 ml, 0.282 mmol), and 1-amino-1-cyclopropanecarbonitrile hydrochloride (0.033 g, 0.282 mmol) in DCM (5 mL) was stirred at room temperature for 12 hours. Purification of the reaction mixture using silica chromatography with ISCO eluting with 0-80% EtOAc/hexanes gave the title compound N-(1-cyanocyclopropyl)-2-((trans-3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclobutyl)amino)thiazole-5-carboxamide (0.060 g, 0.137 mmol, 73.1% yield). m/z: 437 (M+1); 1H NMR (400 MHz, DMSO-d6) δ: ppm 8.78 (s, 1 H) 8.32 (d, J=6.65 Hz, 1 H) 7.93-8.05 (m, 2 H) 7.40 (s, 1 H) 5.18 (quin, J=8.51 Hz, 1 H) 4.31-4.53 (m, 1 H) 3.21-3.41 (m, 2 H) 2.88-3.05 (m, 1 H) 2.29-2.44 (m, 2 H) 1.44-1.60 (m, 2 H) 1.23-1.35 (m, 2 H) 0.93-1.10 (m, 4 H).
Reaction SMILES: [CH3:1][O-].[Na+].CO.CC1C=CC(S([O:16][CH2:17][C@@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[O:19]2)(=O)=O)=CC=1.CO>C(O)(=O)C>[O:16]1[CH2:17][C@@H:18]1[CH2:22][CH2:21][C:20]([O:19][CH3:1])=[O:23]
Reactant: C[O-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCC(=O)O2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CC[C@H]1CO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.7 %

Procedure:
28% Sodium methoxide/MeOH solution (74.0 g, 383.35 mmol) was added to a mixture of (S)-(5-oxotetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (51.81 g, 191.67 mmol) and dehydrated MeOH (280 mL) at room temperature, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was cooled under ice-cooling, and the mixture was neutralized with acetic acid (about 15 mL). The reaction mixture was concentrated to about half-volume under reduced pressure, and ice water (350 mL) was added thereto. Then, the mixture was extracted with a mixed solvent of ethyl acetate/diethyl ether (3:1) (×3). The organic layer was washed successively with aqueous sodium hydrogencarbonate solution, water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude methyl (S)-3-(oxiran-2-yl)propanoate (13.12 g, 101 mmol, 53%) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([C:17]2[N:21]=[CH:20][NH:19][N:18]=2)=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>CN(C)C=O>[CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([C:17]2[N:21]=[CH:20][N:19]([CH2:33][C:32]3[CH:35]=[CH:36][C:29]([F:28])=[CH:30][CH:31]=3)[N:18]=2)=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1cc(-c2nc[nH]n2)sc1C(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2ncn(Cc3ccc(F)cc3)n2)sc1C(=O)NCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
A mixture of N-benzyl-3-methyl-5-(1H-1,2,4-triazol-3-yl)thiophene-2-carboxamide (0.07 g, 0.22 mmol), potassium carbonate (0.03 g, 0.22 mmol) and 4-fluorobenzyl bromide (0.04 mL, 0.33 mmol) in N,N-dimethylformamide (2 mL) was stirred at 80° C. for 2 h. The reaction mixture was allowed to cool to ambient temperature, and then was partitioned between ethyl acetate (75 mL) and water (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 40% ethyl acetate in hexanes to afford the title compound as a yellowish solid (0.054 g, 61%): mp 128-130° C.; 1H NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.45 (s, 1H), 7.37-7.25 (m, 7H), 7.12-7.03 (m, 2H), 6.11 (t, J=5.8 Hz, 1H), 5.30 (s, 2H), 4.61 (d, J=5.8 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 407.2 (M+1).
Reaction SMILES: [OH:1][C@@H:2]([CH3:15])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].[C:16]([NH:26][C@H:27]([C:31](O)=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:16]([NH:26][C@H:27]([C:31]([O:1][C@@H:2]([CH3:15])[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)=[O:4])=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: COc1ccc(COC(=O)[C@H](C)O)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)[C@H](C)OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4methoxybenzyl (S)-(+)-2-hydroxypropionate (7.6 g, 36 mmole), N-CBZ-L-valine (10.05 g, 40 mmole) and DMAP (0.98 g, 8 mmole) in 150 ml dichloromethane was added a solution of DCC (8.3 g, 40 mmole) and the mixture was stirred overnight at room temperature. The mixture was cooled to about 5° C. and the urethane was filtered. The filtrate was evaporated and the product was isolated by silica gel column chromatography. Yield: 14.4 g=90%
Reaction SMILES: [Cl:1][C:2]1([N+:9]([O-])=O)[CH2:6][N:5]([CH3:7])[N:4]=[C:3]1[CH3:8].[ClH:12].[H][H]>[Pt].CO>[ClH:1].[NH2:9][C:2]1[C:3]([CH3:8])=[N:4][N:5]([CH3:7])[C:6]=1[Cl:12]
Reactant: CC1=NN(C)CC1(Cl)[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pt]
Agent: Cl
Solvent: CO
Product: Cc1nn(C)c(Cl)c1N

Procedure:
4-Chloro-1,3-dimethyl-4-nitropyrazole (described in U.S. Pat. No. 3,282,954) (70.0 g.) was dissolved in 900 ml. methanol and 68 ml. concentrated HCl and hydrogenated over 3.2 g. platinum on carbon. After the hydrogen uptake ceased, the catalyst was filtered, the solvent concentrated in vacuum and the residue crystallized from isopropyl alcohol to get 64.15 g. of product, mp 234°-235° C., decomposed.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14])([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(C(=O)O)c1C(=O)O
Reaction time: 13 h
Yield: 84 %

Procedure:
10% Pd/C (2.5 g), 3-nitrophthalic acid (75.0 g, 355 mmol) and ethanol (1.5 L) were charged to a 2.5 L Parr hydrogenator under a nitrogen atmosphere. Hydrogen was charged to the reaction vessel for up to 55 psi. The mixture was shaken for 13 hours, maintaining hydrogen pressure between 50 and 55 psi. Hydrogen was released and the mixture was purged with nitrogen 3 times. The suspension was filtered through a celite bed and rinsed with methanol. The filtrate was concentrated in vacuo. The resulting solid was reslurried in ether and isolated by vacuum filtration. The solid was dried in vacuo to a constant weight, affording 54 g (84% yield) of 3-aminopthalic acid as a yellow product. 1H-NMR (DMSO-d6) δ: 3.17 (s, 2H), 6.67 (d, 1H), 6.82 (d, 1H), 7.17 (t, 1H), 8-10 (br, s, 2H); 13C-NMR (DMSO-d6) δ: 112.00, 115.32, 118.20, 131.28, 135.86, 148.82, 169.15, 170.09.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:41](=[O:47])[O:42][C:43](Cl)(Cl)Cl)Cl.[CH3:49][O:50][C:51]1[CH:52]=[C:53]([CH:59]=[CH:60][CH:61]=1)[O:54][CH2:55][CH2:56]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:42][CH2:43][CH2:56][CH2:55][O:54][C:53]2[CH:59]=[CH:60][CH:61]=[C:51]([O:50][CH3:49])[CH:52]=2)=[CH:18][CH:17]=1
Reactant: COc1cccc(OCCCO)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(OCCCOC(=O)Nc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)c1
Temperature: 25 °C
Yield: 40 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (75 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (114 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(3-methoxyphenoxy)-1-propanol (69 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (51 mg, yield 35%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-])=[CH:5][CH:4]=1)#[N:2].P(Cl)(Cl)([Cl:12])=O.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>>[Cl:12][C:7]1[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][N:6]=1.[Cl:16][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1cc[n+]([O-])cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1ccnc(Cl)c1
Product: N#Cc1ccncc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 24 %
Yield: 30 %

Procedure:
A mixture of 4-cyanopyridine N-oxide (30 g, 0.25 mol), phosphorous oxychloride (96 ml, 0.35 mol) and phosphorous pentachloride (72 g, 0.38 mol) was refluxed at 120°-130° C. for 6 hours and then stirred at room temperature for 12 hours. The reaction mixture was slowly poured into a mixture of ice/Na2CO3 /K2CO3 and was extracted with chloroform (4×250 ml). The solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with 50% ether/hexanes to afford 8.4 g (24%) of 2-chloro-4-cyanopyridine, m.p. 69.5°-70.5° C. and 10.5 g (30%) of 3-chloro-4-cyanopyridine, m.p. 71.5°-72° C.
Reaction SMILES: [C:1]1(=[CH:6][C:7]#[N:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]1([CH3:22])[C:14]([CH3:16])([CH3:15])[O:13][B:12]([C:17]2[CH:18]=[N:19][NH:20][CH:21]=2)[O:11]1.N12CCCN=C1CCCCC2>C(#N)C>[CH3:9][C:10]1([CH3:22])[C:14]([CH3:15])([CH3:16])[O:13][B:12]([C:17]2[CH:21]=[N:20][N:19]([C:1]3([CH2:6][C:7]#[N:8])[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:18]=2)[O:11]1
Reactant: N#CC=C1CCCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1(C)OB(c2cnn(C3(CC#N)CCCC3)c2)OC1(C)C
Temperature: 25 °C
Yield: 17.2 %

Procedure:
A mixture of cyclopentylideneacetonitrile (0.65 g, 0.0061 mol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.60 g, 0.0031 mol, Aldrich, Cat. 525057), and 1,8-diazabicyclo[5.4.0]undec-7-ene (47 mg, 0.00031 mol, Aldrich, Cat. No. 139009) in acetonitrile (7 mL) was stirred at 60° C. overnight. After cooling to r.t., the reaction mixture was concentrated. The crude residue was purified by flash column chromatography on a silica gel column using 40% ethyl acetate in hexane as eluent to afford the desired compound (161 mg, 17.29%). LCMS (M+H)+: m/z=302.4.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=O.[C:13]([NH2:16])(=[S:15])[CH3:14]>CC(C)=O>[ClH:11].[Cl:11][C:7]1[CH:6]=[CH:5][C:4]2[C:3]3[N:16]=[C:13]([CH3:14])[S:15][C:2]=3[CH2:10][C:9]=2[CH:8]=1
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Reactant: CC(N)=S
Solvent: CC(C)=O
Product: Cc1nc2c(s1)Cc1cc(Cl)ccc1-2
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 g of 2-bromo-5-chloroindan-1-one is stirred with 0.31 g of thioacetamide in 100 ml of acetone at room temperature for 5 h. The precipitate is filtered off with suction, washed with acetone and dried in vacuo. The hydrobromide is suspended in ethyl acetate and neutralized with triethylamine, and the ethyl acetate solution is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The free base is dissolved in tetrahydrofuran, and an excess of ethereal HCl is added to this solution. The mixture is stirred at room temperature for 2 h and then concentrated in vacuo. The residue (hydrochloride of 6-chloro-2-methyl-8,8a-dihydroindeno [1,2-d]thiazol-3a-ol) is heated under reflux in 30 ml of glacial acetic acid for 4 h. The solvent is removed in vacuo, the residue is stirred with diisopropyl ether and 6-chloro-2-methyl-8H-indeno[1,2-d]thiazole hydrochloride is obtained with a melting point of 135° C.